Pyrrole, Furan and Thiophene
- Created by: E.H13
- Created on: 25-05-20 14:18
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- Pyrrole, Furan and Thiophene
- Electrophilic Aromatic Substitution
- Strong driving force to restore aromaticity
- Reactions are kinetically controlled in almost cases
- Goes via the lowest energy transition state
- Hammond Postulate
- The TS resembles the Wheland intermediate. Stabilising the intermediate stabilises the TS.
- Reactivity
- 6e over 5 atoms
- Electron rich and therefore react rapidly
- Reaction occurs via 2 position
- Rationalised through resonance forms; 3 vs 2
- Reaction at the heteroatom is strongly disfavoured
- Reaction can occur at 3/4 position if 2 and 5 positions are already substituted
- Order of reactivity; pyrrole > furan > thiophene
- Key factor is effectiveness of overlap of lp on heteroatom and the empty p orbital at positive centre
- Pyrrole is both the most ThD stable and the most reactivity of the series
- This is due to it being to having a low activiation energy due to a stabilised Wheland intermediate
- Reactivity correlates with ability to stabilise intermediate cation
- pKas and that
- 6e over 5 atoms
- Pyrrole
- Protonation
- A weak base; pKa = -3.8
- Occurs at all positions around the ring, but ThD most stable site is C2
- Not beneficial to protonate N; sp3 hybridised means electrons are not delocalised and aromaticity is broken
- Nitration
- Extremely easy - 10^5 more reactive than benzene
- Mild nitrating agent, e.g. acetyl nitrate
- conc. nitric and conc. sulfuric acids decomposes pyrrole
- Preference to 2 position, but can be altered by adding a protecting group
- Tips - triisopropylsilyl
- Remove using TBAF in 100%THF
- Halogenation
- Reactions are easy - hard to prevent over-halogenation
- For pyrrole and furan
- Mono bromination; NBS at low t (-25 to 0oc) in an inert solvent
- NBS = N-bromosuccinimide
- Mild brominating agent
- NBS = N-bromosuccinimide
- Reactions are easy - hard to prevent over-halogenation
- Protonation
- Acylation
- Readily undergoes Friedel-Crafts
- 2 position is most reactive
- Acyl chloride/ anhydride with a Lewis acid catalyst
- No N-acylation
- Vilsmeier reaction
- POCl3, DMF
- See book for mechanisms
- Mannich Reaction
- Formaldehyde (methanal), 2oy amine, H+
- N can be protected using a Boc group
- Boc2O, DMAP, acetonitrile, r.t.
- Mannich Reaction
- Mannich Reaction
- Formaldehyde (methanal), 2oy amine, H+
- Deprotonation
- pKa for pyrrole 17.5
- Can be removed by strong bases
- N can be protected using a Boc group
- Boc2O, DMAP, acetonitrile, r.t.
- pKa for pyrrole 17.5
- Lithiation
- Undergoes lithiation at position 2
- Most electron deficient site
- Due to inductive effects
- Treat with alkyl lithium
- Can be directed to 3 position by first brominating, using bulky protecting group
- Most electron deficient site
- Undergoes lithiation at position 2
- Synthetic Approaches
- Paar-Knorr
- Dehydration under acid condition of 1,4-dicarbonyl
- 1,4-Dicarbonyl
- Paar-Knorr
- Electrophilic Aromatic Substitution
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